1. Field of the Invention
The present invention relates to novel cyclic diamine compounds which have inhibitory effects on both cell adhesion and cell infiltration and are useful as anti-asthmatic agents, anti-allergic agents, anti-rheumatic agents, anti-arteriosclerotic agents, anti-inflammatory agents or the like, and medicines containing such compounds.
2. Description of the Background Art
In various inflammatory diseases, infiltration of leukocytes into inflammatory sites is observed. For example, infiltration of eosinophils into the bronchus in asthma (Ohkawara, Y. et al., Am. J. Respir. Cell Mol. Biol., 12, 4-12 (1995)), infiltration of macrophages and T lymphocytes into the aorta in arteriosclerosis (Sakai, A. et al., Arterioscler Thromb. Vasc. Biol., 17, 310-316 (1997)), infiltration of T lymphocytes and eosinophils into the skin in atopic dermatitis (Wakita H. et al, J. Cutan. Pathol., 21, 33-39 (1994)) or contact dermatitis (Satoh, T. et al., Eur. J. Immunol., 27, 85-91 (1997)), and infiltration of various leukocytes into rheumatoid synovial tissue (Tak, P P. et al., Clin. Immunol. Immunopathol., 77, 236-242 (1995)), have been reported.
Infiltration of these leukocyteds is elicited by cytokines, chemokines, lipids, and complements produced in inflammatory sites (Albelda, S M. et al., FASEB J., 8, 504-512 (1994)). Activated leukocytes adhere to vascular endothelial cells through an interaction called rolling or tethering with endothelial cells activated likewise. Thereafter, the leukocytes transmigrate through endothelium to infiltrate into the inflammatory sites (Springer, T A., Annu. Rev. Physiol., 57, 827-872 (1995)). In adhesion of leukocytes to the vascular endothelial cells in this process, various cell adhesion molecules such as an immunoglobulin superfamily (ICAM-1, VCAM-1 and the like), a selectin family (E-selectin and the like), an integrin family (LFA-1, VLA-4 and the like) and CD44, which are induced on the surfaces of the cells by stimulation by cytokines or the like, play important roles (xe2x80x9cRinsho Meneki (Clinical Immune)xe2x80x9d, 30, Supple. 18 (1998)), and relationship between the disorder state and aberrant expression of the cell adhesion molecules is noted.
Accordingly, an agent capable of inhibiting cell adhesion can be useful as an agent for preventing and treating allergic diseases such as bronchial asthma, dermatitis, rhinitis and conjunctivitis; autoimmune diseases such as rheumatoid arthritis, nephritis, inflammatory bowel diseases, diabetes and arteriosclerosis; and chronic inflammatory diseases. In fact, it has been reported that antibodies against adhesion molecules on leukocytes such as LFA-1, Mac-1 and VLA-4 or antibodies against ICAM-1, VCAM-1, P-selectin, E-selectin and the like on vascular endothelial cells, which become ligands thereof, inhibit infiltration of leukocytes into inflammatory sites in animal models. For example, neutralizing antibodies against VCAM-1 and VLA-4, which is a counter receptor thereof, can delay development of diabetes in an NOD mouse model which spontaneously causes the diabetes (Michie, S A. et al., Curr. Top. Microbiol. Immunol., 231, 65-83 (1998)). It has also been reported that an antibody against VLA-4 or ICAM-1 and its counter receptor, LFA-1, inhibits infiltration of eosinophils in a guinea pig and mouse allergic conjunctivitis model (Ebihara et al., Current Eye Res., 19, 20-25 (1999); Whitcup, S M et al., Clin. Immunol., 93, 107-113 (1999)), and a monoclonal antibody against VCAM-1 inhibits infiltration of leukocytes in a mouse DSS-induced colitis model to attenuate colitis (Soriano, A. et al., Lab. Invest., 80, 1541-1551 (2000)). Further, an anti-VLA-4 antibody and an anti-CD44 antibody reduce the incidence of disease symptoms in a mouse collagen arthritis model (Zeidler, A. et al., Autoimmunity, 21, 245-252 (1995)). Even in cell adhesion molecule deficient-mice, inhibition of infiltration of leukocytes into inflammatory tissues is observed, likewise in inflammatory models (Bendjelloul, F. et al., Clin. Exp. Immunol., 119, 57-63 (2000); Wolyniec, W W. et al., Am. J. Respir. Cell Mol. Biol., 18, 777-785 (1998); Bullard, DC. et al., J. Immunol., 157, 3153-3158 (1996)).
However, it is difficult to develop antibody-based drugs because they are polypeptides and so oral administration is a problem. Moreover, possible side effects due to antigenicity and allergic reactions are problems.
On the other hand, there have been various investigations of low-molecular weight compounds having an inhibitory effect on cell adhesion with a view toward permitting oral administration. These compounds include benzothiophene derivatives (Boschelli, D H. et al., J. Med. Chem., 38, 4597-4614 (1995)), naphthalene derivatives (Japanese Patent Application Laid-Open No. 10-147568), hydroxybenzoic acid derivatives (Japanese Patent Application Laid-Open No. 10-182550), lignans (Japanese Patent Application Laid-Open No. 10-67656), 2-substituted benzothiazole derivatives (Japanese Patent Application Laid-Open No. 2000-086641 through PCT route), condensed pyrazine compounds (Japanese Patent Application Laid-Open No. 2000-319277 through PCT route), 2,6-dialkyl-4-silylphenol (Japanese Patent Application Laid-Open Re-Publication No. 2000-509070 through PCT route) and the like. However, the goal has not often been sufficiently achieved under the circumstances. Cyclic diamine compounds described in Japanese Patent Application Laid-Open Nos. 9-143075 and 11-92382 do not exhibit a sufficient inhibitory effect on cell adhesion, and so there is a demand for further improvement in activity.
An object of the present invention is to provide a substance having inhibitory effects on both cell adhesion and cell infiltration, plus excellent anti-asthmatic effects, anti-allergic effects, anti-rheumatic effects, anti-arteriosclerotic effects and anti-inflammatory effects.
With the foregoing circumstances in mind, the present inventors carried out an extensive investigation to find a substance which inhibits cell adhesion and cell infiltration. As a result, we found that compounds represented by the general formula (1), have excellent cell adhesion-inhibiting effects and cell infiltration-inhibiting effects and are useful as anti-allergic agents, anti-asthmatic agents, anti-rheumatic agents, anti-arteriosclerotic agents or anti-inflammatory agents.
The present invention provides a cyclic diamine compound represented by the following general formula (1): 
wherein
A is (CH2)n, (CH2)nxe2x80x94CHxe2x95x90CH, COxe2x80x94(CH2)n or COxe2x80x94(CH2)nxe2x80x94CHxe2x95x90CH, in which n is a number of 0 to 3; Z represents a formula (2) or (3): 
in which R1, R2 , R4, R5 and R6 are the same or different from one another and individually a hydrogen atom, alkyl group, alkoxy group, halogen atom or nitro group; R3 is a hydrogen atom, alkyl group, alkoxy group, halogen atom, nitro group, naphthyl group, or phenyl group which may be substituted by 1 to 3 substituents selected from alkyl groups, alkoxy groups, halogen atoms, a nitro group and a phenyl group; and X and Y are the same or different from each other and individually CH or a nitrogen atom; and m is a number of 1 or 2;
an acid-addition salt thereof, or a hydrate thereof.
According to the present invention, there is also provided a medicine comprising the above cyclic diamine compound, an acid-addition salt thereof, or a hydrate thereof as an active ingredient.
According to the present invention, there is further provided a medicinal composition comprising the above cyclic diamine compound, the acid-addition salt thereof, or the hydrate thereof and a pharmaceutically acceptable carrier.
According to the present invention, there is still further provided a method for treating a disease caused by cell adhesion and/or cell infiltration, which comprises administering an effective amount of the above cyclic diamine compound, an acid-addition salt thereof, or a hydrate thereof to a patient who requires such treatment.
The alkyl groups represented by R1 to R6 are preferably C1-C6-alkyl groups, and preferable specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl groups, with methyl, ethyl, n-propyl, isopropyl and tert-butyl groups being particularly preferred.
The alkoxy groups represented by R1 to R6 are preferably C1-C6-alkoxy groups, and preferable specific examples include methoxy, ethoxy, isopropoxy, n-butoxy and isobutoxy groups, with methoxy, ethoxy and isopropoxy groups being particularly preferred. The halogen atoms represented by R1 to R6 include chlorine, bromine, fluorine and iodine atoms.
R3 may be a phenyl group which may be substituted by 1 to 3 substituents selected from alkyl groups, alkoxy groups, halogen atoms, a nitro group and a phenyl group, and as examples of the substituents on said phenyl group, may be mentioned the same groups and atoms as the alkyl groups, alkoxy groups and halogen atoms mentioned above.
(CH2)n is preferably methylene, ethylene or trimethylene. (CH2)nxe2x80x94CHxe2x95x90CH is preferably CH2CHxe2x95x90CH, (CH2)2xe2x80x94CHxe2x95x90CH or (CH2)3xe2x80x94CHxe2x95x90CH. COxe2x80x94(CH2)n is preferably CO or COxe2x80x94CH2. COxe2x80x94(CH2)nxe2x80x94CHxe2x95x90CH is preferably COxe2x80x94CHxe2x95x90CH.
Examples of the ring having X and Y in the formula (2) include benzene, pyridine and pyrimidine rings.
No particular limitation is imposed on the acid-addition salts of the compounds (1) according to the present invention so far as they are pharmaceutically acceptable salts. However, examples of the acid-addition salts include acid-addition salts of mineral acids, such as hydrochlorides, hydrobromides, hydriodides, sulfates and phosphates; and acid-addition salts of organic acids, such as benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, oxalates, maleates, fumarates, tartrates, citrates and acetates.
The compounds (1) according to the present invention may be present in the form of solvates typified by hydrates, and the solvates may also be embraced in the present invention.
The compound (1) according to the present invention can be prepared in accordance with, for example, the following process a, b or c:
Process a
A synthetic process in the case where A is (CH2)n or (CH2)nxe2x80x94CHxe2x95x90CH, in which a substituted pyridylmethyl group is introduced into a diamine (9) before introduction of A-Z. 
wherein R7 is a halogen atom, or an alkylsulfonyloxy or arylslfonyloxy group, A1 is (CH2)n or (CH2)nxe2x80x94CHxe2x95x90CH, and m and Z have the same meanings as defined above.
More specifically, ethyl 2-chloroisonicotinate (4) is reacted with 3,4,5-trimethoxyphenylboronic acid (5) at 0xc2x0 C. to reflux temperature, preferably 90xc2x0 C. for 10 minutes to several days, preferably 5 hours in the presence of a metal catalyst such as tetrakis(triphenylphosphine)-palladium(0) in a mixture of a solvent such as toluene, benzene, tetrahydrofuran (THF), dioxane or acetonitrile and 2 M sodium carbonate, thereby obtaining a compound (6). This compound is reacted with lithium aluminum hydride at xe2x88x9220xc2x0 C. to room temperature, preferably 0xc2x0 C. for several seconds to several hours, preferably 30 minutes in THF, thereby giving an alcohol (7). The alcohol (7) is stirred together with thionyl chloride at xe2x88x9220xc2x0 C. to room temperature, preferably 0xc2x0 C. for 1 hour to several days, preferably 5 hours in a solvent such as chloroform, dichloromethane, ethyl acetate, ether, THF or dioxane, thereby obtaining a chloro-derivative (8). The chloro-derivative (8) and a diamine (9) are stirred at room temperature to 100xc2x0 C., preferably 50xc2x0 C. for 1 hour to several days, preferably 5 hours in the presence of potassium carbonate in a solvent such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or acetonitrile, thereby obtaining a mono-substituted compound (10). The compound (10) is condensed with a compound (11), thereby obtaining a compound (1a) according to the present invention. The condensation reaction is conducted by stirring the reactants at room temperature to 100xc2x0 C., preferably 50xc2x0 C. for 1 hour to several days, preferably 5 hours in the presence of potassium carbonate in a solvent such as DMF, DMSO or acetonitrile.
As the halogen atom represented by R7, chlorine or bromine are preferred. As the alkylsulfonyloxy group, a methanesulfonyloxy group is preferred. As the arylsulfonyloxy group, a p-toluenesulfonyloxy group is preferred.
The compound (11) can be prepared in accordance with, for example, the following reaction formula: 
wherein R8 is a hydrogen atom or lower alkyl group, A1 is (CH2)n or (CH2)nxe2x80x94CHxe2x95x90CH, and Z and R7 have the same meanings as defined above.
More specifically, a carboxylic acid or its ester derivative (12) is reduced with a reducing agent such as lithium aluminum hydride to give an alcohol (13). The alcohol is then reacted with a halogenating agent such as thionyl chloride, or a methanesulfonylating agent, thereby obtaining the compound (11). The reduction reaction is conducted in the same manner as described above. The reaction of the alcohol (13) with thionyl chloride in the case of the halogenation, or with methanesulfonyl chloride in the case of the methanesulfonylation is preferably conducted by stirring the reactants at xe2x88x9220xc2x0 C. to room temperature, preferably 0xc2x0 C. for 1 hour to several days, preferably 5 hours in a solvent such as chloroform, dichloromethane, ethyl acetate, ether, THF or dioxane for thionyl chloride or in the presence of a base such as triethylamine or pyridine in a solvent such as chloroform, dichloromethane, ethyl acetate, ether, THF, dioxane or pyridine for methanesulfonyl chloride.
Process b
A synthetic process in the case where A is (CH2)n or (CH2)nxe2x80x94CHxe2x95x90CH, in which a substituted pyridylmethyl group is introduced into a diamine (9) after introduction of A-Z. 
wherein A1 is (CH2)n or (CH2)nxe2x80x94CHxe2x95x90CH, and Z, R7 and m have the same meanings as defined above.
More specifically, a compound (11) is condensed with a diamine (9) to give a mono-substituted compound (14). This compound (14) is reacted with a compound (8), thereby obtaining a compound (1a) according to the present invention. In this reaction, the condensation reaction of the compound (11) with the diamine (9) and the condensation reaction of the compound (14) with the compound (8) can be conducted under the same conditions as in the reactions of the compound (8) and the compound (9).
Process c
A synthetic process in the case where A is COxe2x80x94(CH2)n or COxe2x80x94(CH2)nxe2x80x94CHxe2x95x90CH. 
wherein R9 is a halogen atom or hydroxyl group, A1 is COxe2x80x94(CH2)n or COxe2x80x94(CH2)nxe2x80x94CHxe2x95x90CH, and Z and m have the same meanings as defined above.
More specifically, a compound (15), which is an acid chloride or carboxylic acid, is condensed with a compound (10), thereby obtaining a compound (1b) according to the present invention. The reaction of the acid chloride (15) with the compound (10) is conducted by, for example, stirring the reactants at 0xc2x0 C. to reflux temperature, preferably room temperature for 1 hour to several days, for preferably 5 hours in a solvent such as chloroform or dichloromethane. The reaction of the carboxylic acid (15) with the compound (10) is conducted by, for example, causing the reactants to react at 0xc2x0 C. to reflux temperature, preferably room temperature for 10 minutes to several days, preferably 6 hours in the presence of a dehydration-condensing agent such as dicyclohexyl-carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (water-soluble carbodiimide hydrochloride) or diisopropylcarbodiimide in a solvent such as chloroform or dichloromethane.
The compounds (1) according to the present invention are obtained by any of the above-described processes and may further be purified by using an ordinary purification means such as recrystallization or column chromatography as needed. Also as needed, the compounds may be converted into the desired salts or solvates by methods known in the art.
The compounds (1) according to the present invention, or acid-addition salts or solvates thereof thus obtained have excellent inhibitory effects on cell adhesion as demonstrated in the Examples, which will be described subsequently, and are useful as medicines for treatment or prevention of diseases of animals including humans, such as asthma, allergy, rheumatism, arteriosclerosis and inflammation.
The medicine according to the present invention comprises a compound (1), a salt thereof, or a solvate thereof as an active ingredient. The form of administration may be suitably selected as necessary for the therapeutic application intended without any particular limitation, including oral preparations, injections, suppositories, ointments, inhalants, eye drops, nose drops and plasters. A composition suitable for use in these administration forms can be prepared by blending a pharmaceutically acceptable carrier in accordance with the conventional preparation method publicly known by those skilled in the art.
When an oral solid preparation is formulated, an excipient, and optionally, a binder, a disintegrator, a lubricant, a colorant, a taste corrigent, a smell corrigent and the like are added to compound (1), and the resulting composition can be formulated into tablets, coated tablets, granules, powders, capsules, etc. in accordance with methods known in the art. As such additives described above, any additives may be used which are generally used in the pharmaceutical field. Examples include excipients such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate and polyvinyl pyrrolidone; disintegrators such as dry starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceryl stearate and lactose; lubricants such as purified talc, stearic acid salts, borax and polyethylene glycol; and taste corrigents such as sucrose, orange peel, citric acid and tartaric acid.
When an oral liquid preparation is formulated, a taste corrigent, buffer, stabilizer, smell corrigent and/or the like are added to compound (1), and the resulting composition can be formulated into internal liquid preparations, syrup preparations, elixirs, etc. in accordance with methods known in the art. In this case, vanillin as the taste corrigent, may be used those mentioned above. As the buffer, sodium citrate may be mentioned. As examples of the stabilizer, tragacanth, gum arabic and gelatin may be mentioned.
When an injection is formulated, a pH adjustor, buffer, stabilizer, isotonicity agent, local anesthetic and the like may be added to compound (1) according to the present invention, and the resultant composition can be formulated into subcutaneous, intramuscular and intravenous injections in accordance with methods known in the art. Examples of the pH adjustor and buffer in this case include sodium citrate, sodium acetate and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid. Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride. Examples of the isotonicity agent include sodium chloride and glucose.
When a suppository is formulated, a carrier preparation known in the art, for example, polyethylene glycol, lanoline, cacao butter, fatty acid triglyceride or the like, and optionally, a surfactant such as Tween (trade mark) and the like are added to the compound (1), and the resultant composition can be formulated into suppositories in accordance with methods known in the art.
When an ointment is formulated, a base material, stabilizer, wetting agent, preservative and the like, which are generally used, are blended with compound (1) as needed, and the resulting blend is mixed and formulated into ointments in accordance with known methods known in the art. Examples of the base material include liquid paraffin, white vaseline, bleached beeswax, octyldodecyl alcohol and paraffin. Examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and propyl p-hydroxybenzoate.
Besides the above preparations, inhalants, eye drops and nose drops may also be formulated in accordance with known methods.
The dose of the medicine according to the present invention varies according to the age, weight and condition of the patient to be treated, the administration method, the number of times of administration, and the like. It is however preferred that the medicine is generally orally or parenterally administered at once or in several portions in a dose of 1 to 1,000 mg per day in terms of compound (1), for an adult.
The present invention will hereinafter be described in more detail by the following Examples. However, the present invention is not limited to these examples.
3,4,5-Trimethoxyphenylboronic acid (20.64 g) and ethyl 2-chloroisonicotinate (19.06 g) were suspended in a mixed solvent of toluene (200 mL) and THF (100 mL), and to the suspension 2 M sodium carbonate (200 mL) and tetrakis(triphenylphosphine)palladium(0) (5.93 g) were added. The mixture was stirred overnight at 90xc2x0 C. under an argon atmosphere. Ethyl acetate was added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the title compound.
Yield: 27.70 g (85%).
1H-NMR (400 MHz, CDCl3) xcex4: 1.45(t,3H,J=7.0 Hz), 3.92(s,3H), 3.99(s,6H), 4.46(q,2H,J=7.0 Hz), 7.30(s,2H), 7.76(dd,1H,J=5.1 Hz,1.6 Hz), 8.24(dd,1H,J=1.6 Hz,0.8 Hz), 8.81(dd,1H,J=5.1 Hz,0.8 Hz).
Ethyl 2-(3,4,5-trimethoxyphenyl)isonicotinate (27.70 g) was dissolved in THF (200 mL), and to the solution lithium aluminum hydride (3.31 g) was added at 0xc2x0 C. under an argon atmosphere, and the mixture was stirred at 0xc2x0 C. for 1 hour. A small amount of water and then sodium sulfate were added to the reaction mixture, and the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resultant crude crystals were recrystallized from ethyl acetate-hexane to obtain the title compound.
Yield: 18.15 g (76%).
1H-NMR (400 MHz, CDCl3) xcex4: 3.90(s,3H), 3.95(s,6H), 4.79(s,2H), 7.19(d,1H,J=5.1 Hz), 7.21(s,2H), 7.66(s,1H), 8.60(d,1H,J=5.1 Hz).
4-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine (18.15 g) was dissolved in chloroform (300 mL), and to the solution thionyl chloride (19.2 mL) was added at 0xc2x0 C. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then recrystallized from chloroform-hexane to obtain the title compound.
Yield: 17.87 g (92%).
1H-NMR (400 MHz, CDCl3) xcex4: 3.91(s,3H), 3.97(s,6H), 4.61(s,2H), 7.24(s,2H), 7.26(d,1H,J=5.1 Hz), 7.68(s,1H), 8.67(d,1H,J=5.1 Hz).
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (13.52 g) and piperazine (11.89 g) were dissolved in DMF (100 mL), and to the solution potassium carbonate (15.89 g) was added. The mixture was stirred at room temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, chloroform was added to the residue, and the mixture was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1 to chloroform:ammonia-saturated methanol=10:1) to obtain a free base of the title compound.
Yield: 10.34 g (66%).
1H-NMR (400 MHz, CDCl3) xcex4: 1.56(br,1H), 2.46(br,4H), 2.91(t,4H,J=4.9 Hz), 3.55(s,2H), 3.90(s,3H), 3.97(s,6H), 7.22(d,1H,J=5.1 Hz), 7.24(s,2H), 7.64(s,1H), 8.59(d,1H,J=5.1 Hz).
3,4,5-Trimethoxycinnamic acid (1.5 g) was dissolved in THF (100 mL), triethylamine (0.64 mL) was added to the solution under ice cooling, and ethyl chlorocarbonate (0.44 mL) was then added dropwise thereto. After stirring the resultant mixture at room temperature for 1 hour, sodium borohydride (477 mg) was added to the mixture under ice cooling. After stirring the resultant mixture at room temperature for 1 hour, diluted hydrochloric acid was added to the reaction mixture to conduct extraction with chloroform. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Yield: 736 mg (78%).
1H-NMR (400 MHz, CDCl3) xcex4: 3.85(s,3H), 3.87(s,6H), 4.33(s,2H), 6.29(dt,1H,J=15.8 Hz,5.9 Hz), 6.55(d,1H,J=15.9 Hz), 6.62(s,2H).
3-(3,4,5-Trimethoxyphenyl) -2-propen-1-ol (120 mg) was dissolved in ethanol, and to the solution 10% palladium on carbon (60 mg) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, the filtrate was then concentrated under reduced pressure and extracted with chloroform. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=14:1) to obtain the title compound.
Yield: 44 mg (34%).
1H-NMR (400 MHz, CDCl3) xcex4: 1.82-1.90(m,2H), 2.63(t,2H,J=7.8 Hz), 3.66(t,2H,J=6.4 Hz), 3.79(s,3H), 3.82(s,6H), 6.39(s,2H).
3-(3,4,5-Trimethoxyphenyl)propanol (44 mg) was dissolved in dichloromethane (2 mL), and to the solution pyridine (55.6 mg) was added, and methanesulfonyl chloride (37.4 mg) was added thereto under ice cooling. The mixture was stirred at room temperature for 3 hours. Diluted hydrochloric acid was added to the reaction mixture to conduct extraction with chloroform. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (chloroform:methanol=40:1) to obtain the title compound.
Yield: 50 mg (85%).
1H-NMR (400 MHz, CDCl3) xcex4: 2.01-2.08(m,2H), 2.67(t,2H,J=7.5 Hz), 2.99(s,3H), 3.80(s,3H), 3.82(s,6H), 4.21(t,2H,J=6.2 Hz), 6.38(s,2H).